Germinal Matrix-Intraventricular Hemorrhage: a Tale of Preterm Infants

Hindawi International Journal of Pediatrics Volume 2021, Article ID 6622598, 14 pages https://doi.org/10.1155/2021/6622598

Review Article Germinal Matrix-Intraventricular Hemorrhage: A Tale of Preterm Infants

Walufu Ivan Egesa ,1 Simon Odoch,1 Richard Justin Odong,1 Gloria Nakalema,1 Daniel Asiimwe ,2 Eddymond Ekuk,3 Sabinah Twesigemukama,1 Munanura Turyasiima ,1 Rachel Kwambele Lokengama,1 William Mugowa Waibi ,1 Said Abdirashid,1 Dickson Kajoba,1 and Patrick Kumbowi Kumbakulu1

1Department of Paediatrics and Child Health, Faculty of Clinical Medicine and Dentistry, Kampala International University, Uganda 2Department of Surgery, Faculty of Clinical Medicine and Dentistry, Kampala International University, Uganda 3Department of Surgery, Faculty of Medicine, Mbarara University of Science and Technology, Uganda

Correspondence should be addressed to Walufu Ivan Egesa; [email protected]

Received 20 December 2020; Accepted 26 February 2021; Published 16 March 2021

Academic Editor: Somashekhar Marutirao Nimbalkar

Copyright © 2021 Walufu Ivan Egesa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is a common intracranial complication in preterm infants, especially those born before 32 weeks of gestation and very-low-birth-weight infants. Hemorrhage originates in the fragile capillary network of the subependymal germinal matrix of the developing brain and may disrupt the ependymal lining and progress into the lateral cerebral ventricle. GM-IVH is associated with increased mortality and abnormal neurodevelopmental outcomes such as posthemorrhagic hydrocephalus, cerebral palsy, epilepsy, severe cognitive impairment, and visual and hearing impairment. Most aﬀected neonates are asymptomatic, and thus, diagnosis is usually made using real-time transfontanellar ultrasound. The present review provides a synopsis of the pathogenesis, grading, incidence, risk factors, and diagnosis of GM-IVH in preterm neonates. We explore brief literature related to outcomes, management interventions, and pharmacological and nonpharmacological prevention strategies for GM-IVH and posthemorrhagic hydrocephalus.

1. Introduction found no significant improvement in survival without neonatal and long-term morbidity among VLBW infants between Germinal matrix-intraventricular hemorrhage (GM-IVH) 1997 and 2002. remains a devastating neurological complication with considerable mortality [1] and neurodevelopmental disability 2. Anatomy and Pathogenesis of GM-IVH [2]. Hemorrhage originates in the capillary network of the subependymal germinal matrix (GM) of the developing brain The GM is located in the subependyma of the ventricular and may disrupt the ependymal lining and progress into the walls. It gives origin to the cerebral neuroblasts and glia, is lateral cerebral ventricle [3, 4]. Although significant strides in highly cellular and gelatinous, and is richly vascularized by obstetrics and neonatal medicine have led to improved sur- capillaries that are poorly supported by muscle or collagen vival of preterm infants with lower gestational age and birth [11]. Vascularization of the GM is prominent from 7-8 weight [5–7], we seem to have reached the nib of our ability weeks of gestation and persists into the beginning of the to ensure morbidity-free survival of very-low-birth-weight third trimester [12, 13]. The thickness of the GM decreases (VLBW) infants in advanced care settings [8, 9]. In the after 24 weeks of gestation and almost disappears by 36–37 United States, for example, Fanaroff and colleagues [10] weeks [11]. Animal studies showed that the characteristic 2 International Journal of Pediatrics architecture of the subependymal matrix as the border zone lation in neonatal intensive care units (NICUs), later declin- between cerebral arteries and the collection zone of the ing by three quarters to 12.5% in 2005, probably as a result of deep cerebral veins makes it susceptible to focal hypoxic improvements in ventilators, and the introduction of surfac- changes [13]. tant and corticosteroids. Based on age at onset, almost 40.6% The pathogenesis of GM-IVH is intricate and multifacto- of low-birth-weight (<2.5 kg) preterm neonates develop GM- rial, but mostly attributed to the combined fragility of the IVH within the first 3 days of life, 50% by day 5, and 71.5% by primitive GM vasculature, fluctuations in cerebral blood flow day 7 [28]. (CBF) due to low mean arterial pressure, and impaired cerebral autoregulation in clinically unstable preterm neonates 5. Risk Factors for Development and [12, 14, 15] which increases the likelihood of vascular rup- Progression of GM-IVH ture, resulting in hemorrhage that may either be restricted to the GM or extends to the adjacent lateral ventricle. Hyp- Various pre-, peri-, and postnatal factors have been impli- oxia in the GM triggers upregulation and expression of cated as independent risk factors for GM-IVH in preterm growth factors VEGF and angiopoietin-2 which induce neonates. These include in vitro fertilization, absence of ante- angiogenesis. This consequently leads to formation of fragile natal care, lack of maternal prenatal steroid administration, nascent vessels that lack pericytes, display immature basal chorioamnionitis, multiple gestation, HIV exposure, fetal lamina low in fibronectin, and have astrocyte end-feet cover- distress, vaginal delivery, outborn status, male gender, lower age that is deficient in glial fibrillary acidic protein [11, 16]. In gestational age and birth weight, resuscitation at birth, deliv- addition, platelet or coagulation disorders may accentuate ery room intubation, anemia (low hematocrit), and blood the hemorrhage [11]. Hemorrhagic parenchymal infarction transfusion [22, 25, 26, 28–35]. Other risk factors include is thought to occur when venous occlusion from a hematoma clinically significant patent ductus arteriosus [36], pneumo- impairs perfusion in the periventricular white matter [17]. thorax [33, 37], higher fraction of inspired oxygen (FiO2) during the first 24 hours, early- and late-onset sepsis [31, 3. Grading of GM-IVH 33], postnatal hydrocortisone administration for hypotension, inotrope use [29, 34, 38], respiratory distress syndrome Grading systems developed by Papile et al. [18] and Volpe are requiring mechanical ventilation, hyponatremia, hyperglyce- the most widely accepted, although several others exist [19]. mia [32], hypercapnia [36, 38], and severe metabolic acidosis Using computed tomography scan, Papile et al. [18] devel- [34, 39]. Studies have also indicated that preterm neonates oped a four-grade classification of GM-IVH based on the born at lower health facilities [34] and those transferred to location and severity of hemorrhage. Grade I is defined by another hospital after birth [25, 40] are more likely to develop hemorrhage that is confined to the GM, grade II by extension GM-IVH. As such, women in preterm labor should be trans- of hemorrhage into lateral ventricles without ventricular dila- ported to a tertiary health facility that specializes in high-risk tation, grade III when ventricular hemorrhage is present in deliveries [38]. Equally significant are genetic risk factors such addition to ventricular dilatation, whereas grade IV is defined as factor V Leiden (Arg506Gln), prothrombin (G20210A) by the presence of parenchymal hemorrhage [18]. A similar gene mutations, and methylenetetrahydrofolate reductase grading system by Volpe is based on cranial ultrasound scan (MTHFR 1298A>C) polymorphism [24, 41, 42]. These risk (CUS). Grade I refers to hemorrhage confined to the sube- factors are summarized in Table 1. pendymal GM, and grade II as hemorrhage within the lateral A proportion of preterm neonates with previously diag- ventricle without ventricular dilation and/or hemorrhage nosed mild GM-IVH may deteriorate to severe GM-IVH. occupying less than 50% of the ventricle. Grade III hemor- Several risk factors including maternal lower genital tract rhage is defined by ventricular dilation and/or hemorrhage infection, lower gestational age [43], necrotizing enterocolitis occupying more than 50% of the ventricle, while grade IV (NEC), and thrombocytopenia [44] have been documented. is ventricular hemorrhage extending into the surrounding parenchyma [20]. This is illustrated in Figure 1. Mild 6. Clinical and Laboratory GM-IVH refers to grade I and II hemorrhage, while severe Characteristics of GM-IVH GM-IVH is a term used to refer to grade III and IV hemorrhage [21]. The majority of cases of GM-IVH are clinically silent [23, 45] and only detectable by routine brain imaging. Symptomatic 4. Incidence of GM-IVH neonates may manifest with convulsions, bulging fontanel, recurrent apnea, unexplained pallor, respiratory distress, The global incidence of GM-IVH among preterm infants and temperature instability [46, 47]. Clinically identifiable ranges from 14.7% to 44.7% [22–25], with considerable vari- seizures are reported more often among neonates with grade ation across gestational age groups, neonatal intensive care IV GM-IVH [48]. units, and countries [6, 22, 25, 26]. Hefti et al. [27] examined A significant reduction in the hematocrit may occur in for GM-IVH in 345 preterm neonates autopsied from 1914 the presence of a large hemorrhage [17]. Biomarkers for early to 2015 at Boston Children’s Hospital in the United States prediction and detection of neuronal injury in neonates have of America. The incidence of GM-IVH was 4.7% before the gained clinical value in recent decades. This is because early 1960s and increased to 50% from 1975 to 1980 following diagnosis may provide a crucial window for implementation the introduction of novel positive pressure mechanical venti- of neuroprotective interventions which may translate into International Journal of Pediatrics 3

Lateral ventricle Lateral Germinal Brain Hemorrhage confned to ventricles matrix parenchyma the germinal matrix

Normal sagittal view Normal coronal view Grade I through the brain through the brain

Extension of Intraventricular Extension of hemorrhage Intraventricular extension hemorrhage into a or extension involving into the surrounding involving <50% of the dilated ventricle >50% of the ventricle parenchyma ventricle

Grade II Grade III Grade IV

Figure 1: Grades of GM-IVH.

Table 1: Risk factors for GM-IVH in preterm infants.

(i) In vitro fertilization [30, 33] (ii) No antenatal care [31, 32] (iii) Lack of prenatal corticosteroid administration [25, 29, 31, 33, 34] (iv) Chorioamnionitis [35, 36] Prenatal (v) Multiple gestation [30] (vi) Low gestation age [32] (vii) Maternal HIV [28] (viii) Inherited coagulation abnormalities [24, 41, 42] (i) Fetal distress [22] (ii) Vaginal delivery [25, 38] (iii) Extreme prematurity [25, 28, 36] Perinatal (iv) Very low birth weight [28, 36] (v) Low 5-minute APGAR score and resuscitation at birth [25, 31, 36, 38] (vi) Intubation and mechanical ventilation [25, 31, 32, 38] (vii) Male sex [22, 26] (i) Neonatal transfer after birth [22, 25, 28, 34, 38, 40] (ii) Medication (e.g., inotropes, hydrocortisone, sodium bicarbonate, normal saline boluses, and opioids) [29, 36, 38] (iii) Anemia [29] (iv) Blood transfusion [28, 32] (v) Neonatal sepsis [31, 33, 36] (vi) Patent ductus arteriosus [29, 31, 36] (vii) Respiratory distress syndrome [32, 36] Postnatal (viii) Hypercapnia [36, 38] (ix) High fraction of inspired oxygen during the first 24 hours [33] (x) Pneumothorax [33, 37] (xi) Hypotension [34, 38] (xii) Hyponatremia [32] (xiii) Hyperglycemia [32] (xiv) Metabolic acidosis [34, 39] 4 International Journal of Pediatrics improved outcomes. Investigators have proposed several bio- CUS result was abnormal [53]. In 2020, the American Acad- markers including S100β, activin A, adrenomedullin, eryth- emy of Pediatrics [58] recommended CUS for all preterm ropoietin, neuron-specific enolase, oxidative stress markers, infants born at ≤30 weeks or >30 weeks of gestation with sig- glial fibrillary acidic protein, and creatine phosphokinase nificant risk factors. The initial CUS should be performed BB (CPK-BB). Among these metabolites, elevated S100β within the first 7-10 days, with subsequent scans at 4-6 weeks levels in the blood and urine and activin A levels in the blood of life and at term corrected age or prior to discharge. Serial are the most promising [49, 50]. CUS should be performed for infants with abnormal CUS findings, adjusted according to the clinical state. 7. Cranial Ultrasound 8. Magnetic Resonance Imaging 7.1. The Role of CUS. Since the late 1970s, high-resolution real-time cranial ultrasound (CUS) has been the cornerstone Magnetic resonance imaging (MRI) is superior to ultrasound for diagnosis of GMH-IVH [51], with a sensitivity and spec- at detecting white matter abnormalities, hemorrhagic, and ificity of 96% and 94%, respectively, for detecting intracranial cystic lesions [61]. Although MRI is increasingly being uti- hemorrhage [52]. Worldwide, CUS remains the most readily lized, it is not readily available, requires the neonate to be available and widely used neuroimaging modality in NICUs sedated, and may be unsuitable for unstable severely ill [53, 54]. Most importantly, CUS is portable, reliable, cost- infants. Nonetheless, some institutions have demonstrated effective, noninvasive, and radiation-free, and does not that MRIs may be performed without sedation of the neonate require any special preparation [53, 55, 56]. However, the at term equivalent age [62, 63]. MRI may be performed at findings are operator-dependent, and subtle lesions may be term corrected age for infants whose CUS reveals moderate missed [53]. The anterior fontanelle is the most commonly to severe abnormalities such as grade III/IV GM-IVH, post- used site, but an acoustic window through the posterior and hemorrhagic ventricular dilatation (PHVD), or grade III/IV mastoid fontanelles can significantly augment the findings periventricular leukomalacia (PVL), when clinical risk for [57, 58]. CUS can be performed at the bedside and in the white matter infarction (WMI) is increased or when parental incubator, within less than 5 minutes and without significant reassurance is needed [12, 53]. manipulation of the infant [55]. Sonographic abnormalities should be correlated on both 9. Clinical Outcomes coronal and parasagittal views, and findings on the left and right sides should be graded separately, and the location, size, According to Wu et al. [43], 8.2% of preterm neonates (<32 and extent of the lesions are noted [59]. Interpretation of weeks) with grade II/III GM-IVH deteriorate within 7 days ventricular width should be done with consideration of the to grade III/IV GM-IVH. Moreover, the mortality associated gestational age-specific reference ranges, as determined by with GM-IVH remains unacceptably high, even within Levene in 1981 [60]. NICUs manned by neonatologists. At least one-fifth to one- third of preterm neonates with GM-IVH die during hospital- 7.2. When Should CUS Be Performed? The timing of screen- ization [24, 64], with almost 86% to 100% of deaths occurring ing varies depending on the protocol adopted, although con- within the first postnatal week [23, 65]. Generally, mortality sensus seems to have been reached regarding the screening of increases exponentially with increasing grades [23], given all preterm neonates born before 32 weeks of gestation that 4%, 10%, 18%, and 40% of preterm neonates with grades and/or those with VLBW [53, 58]. Nonetheless, most cases I-IV, respectively, die during the first hospital admission of GM-IVH occur during the first week of life [23, 28], which [66]. Survivors are more likely to have a prolonged duration guides the timing of serial CUS screening. It is important to of hospital stay, which imposes a significant financial burden note that GM-IVH may be progressive [28], and the grade to the health system [66]. may change over time, justifying the need for CUS screening Recent evidence shows that any grade of hemorrhage over multiple time points. In the 1980s, the initial CUS was may be associated with abnormal neurodevelopmental out- performed during the first 3 days of life, often within 24 comes, although adverse outcomes have often been linked hours, repeated a week later among survivors, and weekly to severe GM-IVH [2, 67–70] and lower gestational age [6, thereafter as indicated [54]. In Europe, diagnosis of GM- 68]. Survivors are likely to develop neurodevelopmental IVH is made by performing a bedside real-time CUS, usually problems such as PHVD [71], visual and hearing impair- on day 1, 3, 7, 14, and 28, although regular scanning may be ment, severe cognitive impairment, cerebral palsy (CP), neu- indicated [59]. Recent Canadian guidelines recommend rou- rodevelopmental delay, and epilepsy [2, 67, 68, 70, 72, 73]. tine CUS for all neonates born at <32 weeks between days 4 According to Christian et al. [66], 9% of preterm neonates and 7 of life or earlier depending on the clinical state of the with GM-IVH develop posthemorrhagic hydrocephalus preterm infant. Neonates born at ≥32 to <37 weeks are sim- (PHH). Among these, 1%, 4%, 25%, and 28% of patients with ilarly investigated only if additional risk factors such as com- grades I-IV hemorrhage develop PHH, respectively. Com- plicated monochorionic twin gestation, microcephaly, need municating PHH accounts for most cases, thought to occur for critical care, sepsis, NEC, major surgery, and/or abnormal due to mechanisms such as impaired CSF reabsorption neurological symptoms are present. Repeat imaging is per- which accompanies obliteration of the arachnoid villi by formed at 4 to 6 weeks of life for all neonates born at <32 microthrombi with subsequent inflammation and fibrosis weeks and for ≥32 to <37 weeks of gestation if the first [74]. Noncommunicating hydrocephalus is theorized to International Journal of Pediatrics 5 occur due to acute obstruction of the foramen of Monro or the no difference between conservative management and serial aqueduct by a blood clot or due to subependymal scarring [75]. tapping of CSF via lumbar puncture or ventricular tapping as regards to reduced risk of major disability, multiple dis- 10. Management of GM-IVH ability, death, or need for permanent shunt placement [85]. Needless to say, repeated ventricular punctures inflict a new 10.1. General Strategies. Management of GM-IVH is focused injury to the frontal lobe with each puncture and may on addressing systemic issues of the neonate such as blood increase infection risk [86]. pressure and respiratory status, which might influence progression of hemorrhage. Screening for sequelae of GM-IVH 11.2. Surgical Strategies should be performed, and necessary interventions are done, including management of hypotension, shock, ane- 11.2.1. DRIFT. DRIFT involves the insertion of right frontal mia, and metabolic acidosis through judicious use of intra- and left occipital catheters, with intraventricular injection of venous fluids and blood transfusion. Continuous EEG or tissue plasminogen activator (e.g., urokinase) that is insuffi- amplitude-integrated EEG monitoring is indicated in the cient to produce a systemic effect [87, 88]. After 8 hours of presence of seizures [17]. TPA injection, irrigation with artificial CSF is commenced at a rate of 20 ml/hour, under ICP monitoring, with the goal 10.2. Mesenchymal Stem Cell Therapy. Animal models [76] of maintaining a pressure < 7 mmHg. The drainage fluid and phase I randomized controlled trials (RCTs) involving clears over about 72 hours, from a dark-colored thick fluid extremely preterm infants [77] have documented the promis- to straw-colored CSF [87]. The DRIFT approach is associated ing therapeutic potential of intraventricular transplantation with secondary hemorrhage and does not reduce mortality of allogenic mesenchymal stem cells (MSCs) in severe GM- neither does it alter the need for permanent shunt placement IVH. This novel therapy is thought to attenuate brain injury [89, 90]. Contrastingly, studies have shown a reduction in following GM-IVH and prevent the development of PHH. severe cognitive disability among survivors at 2 years of life Current evidence is weak, and thus, more human clinical tri- [90] and at 10 years of life [91]. When performed within als are needed to provide a stronger body of evidence regard- three weeks of IVH onset in extremely-low-birth-weight ing the therapeutic benefits and harms of MSCs [78]. (ELBW) neonates, fibrinolytic therapy followed by external Nevertheless, a phase 2 RCT [79] to evaluate the efficacy ventricular drainage may significantly reduce the need for and safety of umbilical cord blood-derived MSCs (Pneumos- permanent shunt surgery, without increasing the risk of tem®) in 23 to <34 weeks’ gestation preterm neonates with secondary hemorrhage and infections [88]. Despite the severe GM-IVH is ongoing. The primary outcomes of the shortcomings, DRIFT is cost-effective [91] and remains a study are death or shunt operation up to a postmenstrual suitable therapy [83]. age of 40 weeks. 11.2.2. Shunts. Neurosurgical intervention criteria, choice, 11. Management of PHVD and PHH and timing of temporizing CSF diversion techniques for PHH vary across centers [81, 92]. Children with shunts from Due to lack of strong evidence at the moment, there are no prematurity have been observed to require one or more shunt standardised protocols for treatment of PHVD and PHH revisions and to develop slit ventricle syndrome, loculated [80], and optimal timing of interventions is still contentious hydrocephalus, and shunt infections more often than chil- [81]. Nonetheless, a low threshold for intervention has been dren with hydrocephalus due to other etiologies [93, 94]. linked to lower odds of death and poor neurodevelopmental outcomes [82]. Management of PHVD generally is aimed at (1) Ventricular Reservoir. A ventricular reservoir (VR), also preventing secondary damage due to raised intracranial pres- known as a ventricular access device (e.g., Ommaya reservoir sure (ICP) and avoiding the need for a permanent shunt and McComb reservoir), is a temporizing treatment for PHH which may be associated with complications such as blockage in preterm infants [86, 93, 95] that may even eliminate the and infection [71]. Several therapeutic options have been need for a permanent shunt in some cases [96–98]. It studied over decades, including conservative management, fl involves the placement of a ventricular catheter into the right diuretic therapy, repeated cerebrospinal uid (CSF) tapping lateral ventricle that is then connected to a subcutaneous res- to control excessive expansion, and drainage, irrigation, and fi ervoir from which CSF is intermittently aspirated percutane- brinolytic therapy (DRIFT) [72, 83]. ously to remove CSF and maintain a stable clinical state which includes normal increase of head circumference, soft 11.1. Nonsurgical Strategies fontanel, and CUS [86, 97]. As described by Kuo [86], aspira- 11.1.1. Diuretics. Available evidence has proven that medical tion of the reservoir is accomplished using a scalp needle of therapy with diuretics such as furosemide and acetazolamide 25-gauge or smaller, with the infant in the supine position. is inefficient, because it is associated with increased mortality How often and how much CSF is aspirated depends on the and neurologic outcomes, and does not reduce the need for opening and closing pressures, respectively. VR was per- shunt placement [72, 84]. formed as the initial procedure in 50 (54.9%) of the 91 preterm neonates who were surgically treated for PHH at 11.1.2. Repeated Tapping of CSF. A Cochrane review of three Children’s Hospital Los Angeles between 1997 and 2012 randomized controlled trials (RCTs) and a quasi-RCT found [93]. As many as 57% of patients experience complications 6 International Journal of Pediatrics

Table 2: Strategies for prevention of GM-IVH in preterm neonates.

Prenatal Perinatal Postnatal Avoid interhospital transport Elevated midline head positioning Delivery at a tertiary hospital Minimize handling and stimulation Prevent preterm birth Prompt delivery upon recognition Fluid therapy for hypotension Corticosteroids of fetal distress Near-infrared spectroscopy monitoring of cerebral oxygenation Delayed cord clamping Prevent and treat NEC and sepsis Erythropoiesis stimulation agents (e.g., erythropoietin and darbepoetin) such as skin breakdown, ventricular hemorrhage, CSF infec- infection [96, 106] predominantly caused by Staphylococcus tion, and leak [99]. Apnea and ventriculitis have also been species [105]. documented [98]. Repeated tapping from a VR has been shown not to increase the risk of reservoir infection [95]. A 12. Prevention of GM-IVH prospective multicenter cohort of VLBW neonates with severe GM-IVH observed no difference in infection rates To protect the preterm brain from GM-IVH, a multifaceted between VR and ventriculosubgaleal shunts (17% versus approach addressing specific antenatal, delivery room, post- 14%, p =0:71) [92]. natal, and NICU factors should be implemented (Table 2) [111, 112]. Since GM-IVH is primarily linked to increased (2) Ventriculosubgaleal Shunt. Ventriculosubgaleal shunt vascular fragility and disturbance in CBF, strategies are (VSGS) placement provides a temporary treatment of PHH directed to strengthening the GM microvasculature and to in medically unstable infants and also averts the need for stabilizing the CBF. repeated tapping of CSF [100]. Through a small scalp inci- 12.1. Prevent Preterm Birth. Measures that target prevention sion near the anterior fontanelle, under local anesthesia and of preterm birth are the most important strategies for mini- mild sedation, a ventricular catheter is carefully placed into mizing the occurrence of GM-IVH [21]. Preterm birth may the lateral ventricle and anchored to the dura. Blunt dissec- be spontaneous or induced in situations such as eclampsia. tion is performed to create a pouch between the periosteum Unless medically indicated, preterm birth can be delayed by and galea, creating a subgaleal pouch where the outermost evidence-based approaches such as antenatal progesterone (proximal) end of the ventricular catheter is placed to allow supplementation from 16 to 24 weeks through 34 weeks of for CSF drainage [86, 101, 102]. The procedure is described gestation in women with a current singleton pregnancy and in a recent publication by Kuo [86] and can be safely accom- previous spontaneous delivery, and those with a short cervi- plished in the NICU or the operating theatre [101, 103]. Col- cal length (≤20 mm before 24 weeks’ gestation). Other inter- lection of CSF in the subgaleal space can result in a ventions such as avoidance of tobacco smoking during cosmetically unappealing scalp swelling [104]. VSGS has pregnancy, cervical cerclage for cervical incompetence, toco- been associated with recurrent meningitis, subgaleal adhe- lytics for preterm labour, and dedicated preterm birth pre- sions, shunt obstruction requiring ventricular catheter revi- vention clinics have been utilized [113, 114]. sion or renewal, CSF leakage, and slippage of the catheter into or out of the ventricle [101, 102, 105]. It is estimated that 12.2. Prenatal Corticosteroids. The World Health Organiza- 12% of patients with VSGS require a permanent ventriculo- tion [115] strongly recommends prenatal corticosteroid use peritoneal shunt [101], which if needed is often placed when for all women at 24 to 34 weeks’ gestation for whom preterm the CSF protein content decreases to <2 g/l, with a cell count birth is imminent. Several studies have shown that the inci- μ <100 cells/ l and negative CSF culture for bacteria [102]. dence of GM-IVH and white matter injury can be significantly reduced by the administration of a short course of (3) Permanent Ventriculoperitoneal and Ventriculoatrial prenatal corticosteroids such as betamethasone or dexameth- Shunt. Permanent ventriculoperitoneal shunt (VPS) or ven- asone [22, 31, 33, 38, 116, 117]. This protective effect may be triculoatrial shunt (VAS) placement is often performed after linked to a reduction in the incidence and severity of RDS failure of the initial temporizing measures discussed earlier [118] and NEC [119]. Prenatal corticosteroids have also been [96, 106]. Of the 21% to 36% of preterm LBW neonates with observed to stabilize the GM vasculature through suppres- – GM-IVH who subsequently develop PHH [107 109], up to sion of vascular endothelial growth factor and increased 18% to 39% require permanent VPS placement [64, 66, transforming growth factor-β (TGF-β) levels in animal stud- 109]. Whitelaw and Aquilina [110] suggested VPS placement ies. This results in angiogenic inhibition, trimming of neovas- when ventricular enlargement continues at a body weight of culature, and enhanced pericyte coverage, and consequently, a fl around 2.5 kg and cerebrospinal uid protein levels are below reduced propensity for hemorrhage [120]. 1.5 g/l. On the other hand, complications associated with shunts are not uncommon, often leading to prolonged hospi- 12.3. Prenatal Magnesium Sulphate. Magnesium sulphate talization. These include overdrainage, shunt blockage often (MgSO4) is widely used for the prevention and management requiring one or more shunt revisions or replacement, and of eclampsia. A meta-analysis of 6 RCTs and 5 cohort studies International Journal of Pediatrics 7 conducted between 1995 and 2004 provided evidence that there was no difference in adverse neurosensory outcomes at MgSO4 administered to women at high risk of preterm 18 months of life. In addition, a multicenter double-blind labor provides significant neuroprotection against moderate RCT showed that administration of prophylactic ibuprofen to severe CP, without causing adverse effects on the infants within the first 6 hours of birth was ineffective against pre- [121]. The World Health Organization, American College venting grade II to IV GM-IVH [143]. Therefore, both indo- of Obstetricians and Gynecologists (ACOG), and the Soci- methacin and ibuprofen are not recommended for ety for Maternal-Fetal Medicine currently recommend the prevention of GM-IVH, but are reserved for treatment of use of MgSO4 for women at risk of imminent preterm birth patent ductus arteriosus. before 32 weeks of gestation for prevention of cerebral palsy during infancy and childhood [122, 123]. Compared 12.7. Midline Head Positioning and Head Tilting. Midline to controls, MgSO4 has not been found to reduce the rates (neutral) head positioning is thought to optimize cerebral of GM-IVH [124]. venous drainage through the internal jugular veins, which are the major outflow paths for cranial blood. Head rotation 12.4. Delivery at Tertiary Center and Avoidance of to either side may result in ipsilateral occlusion or obstruc- Interhospital Transport. Evidence from a large retrospective tion of the jugular venous drainage system [144]. Near- analysis of 67,596 VLBW preterm neonates found a correla- infrared spectroscopy (NIRS) shows that midline head tion between interhospital transport and increased incidence position and head tilting (elevating the head of the incubator and severity of GM-IVH [40], which has been linked to upwards by 15–30°) facilitates hydrostatic cerebral venous increased head and torso vibrations during neonatal trans- outflow in preterm infants [145, 146]. Moreover, Doppler port [125]. A cohort study of 5,712 infants born at 24–30 ultrasonography studies showed that occlusion of the jugular weeks in the Australian and New Zealand Neonatal Network venous system by changes in head position results in large from 1995–97 found that infants transferred to another hos- alterations in blood flow velocities in the superior sagittal pital after birth had 1.60 times higher odds of developing sinus, increased cerebral blood volume, and ICP [145, 147, severe GM-IVH (95% CI: 1.15 to 2.21, p <0:01) [22]. There- 148] which may result in GM-IVH. Head positioning and fore, when high-risk preterm delivery is anticipated, it should tilting has been reported to have no effect on cerebral hemo- be conducted in a tertiary center [38, 126]. dynamics and oxygenation in preterm infants [149] which contrasts the findings of other studies [148]. Recent system- 12.5. Delayed Cord Clumping. Delayed cord clamping (DCC) atic reviews and meta-analyses [149, 150] reported inconclu- results in a higher hematocrit [127–129], superior vena cava sive evidence that head positioning prevents the occurrence blood flow, right ventricle output, and right ventricular and extension of GM-IVH. However, a single-center study stroke volume [130], higher blood pressure and admission [151] found that placing <28 weeks’ gestation infants in the temperature [127], less delivery room resuscitation [128], elevated midline head position for the first 96 h of life is asso- and reduced early red blood cell transfusion [131, 132]. ciated with a reduced risk of grade IV GM-IVH and mortality DCC has been shown to be beneficial in preventing GM- during hospitalization. IVH [129, 131, 132], NEC [133], and mortality [131], and can be safely implemented in singleton and monochorionic, 12.8. Preventing Necrotizing Enterocolitis. NEC is associated dichorionic, and trichorionic multiple preterm gestations with persistently lower cerebral tissue oxygenation [152]. [134]. The optimal duration for cord clamping remains con- There is established evidence that human breast milk troversial. For preterm and term neonates not requiring [153], probiotics [154], and bovine lactoferrin supplemen- resuscitation at birth, the American College of Obstetricians tation [155, 156] reduce the risk of NEC. The precise and Gynecologists, American Academy of Pediatrics, and effects of the latter on the incidence of NEC are being stud- American College of Nurse-Midwives recommend at least a ied by large multicenter RCTs such as the lactoferrin infant 30-60-second delay to clamp the cord [135], whereas the feeding trial (LIFT) in New Zealand, Australia [157], and World Health Organization strongly recommends a 60- Canada [158]. 180-second delay [136]. 12.9. Near-Infrared Spectroscopy Monitoring of Cerebral 12.6. Postnatal Indomethacin or Ibuprofen. Studies per- Oxygenation. NIRS is a real-time, continuous, and noninva- formed on beagle pups [137] suggested that postnatal intra- sive technique similar to pulse oximetry. The device uses venous administration of indomethacin may confer infrared light to penetrate living tissue and estimate brain tis- protection against GM-IVH by stimulating basement mem- sue oxygenation by measuring the absorption of infrared brane deposition in the GM microvasculature. Although light, according to Beer-Lambert law [159, 160]. Cerebral early low-dose prophylactic indomethacin in VLBW preterm oxygen saturation monitoring using NIRS has become a clin- infants has not been independently associated with adverse ically useful practice because systemic arterial oxygenation neurodevelopmental function [73, 138], evidence regarding does not always reflect cerebral oxygenation [161]. In a a reduction in the incidence of GM-IVH has been controver- recent multicenter study of 103 neonates born at a mean ges- sial [139–141]. One multinational RCT of extremely-low- tational age of 26 weeks and birth weight < 1250 g, Chock birth-weight neonates found that early indomethacin- and associates [162] found a clinically significant association prophylaxis reduces the incidence of patent ductus arteriosus between low cerebral oxygen saturation using NIRS in the and severe GM-IVH [142]. Compared to the placebo group, first 96 hours of life and abnormal cranial ultrasonographic 8 International Journal of Pediatrics

findings. Thus, cerebral oximetry can be used to monitor which survival of smaller infants was low. As such, further high-risk infants such that timely interventions are taken to research is required, before a recommendation can be made. improve cerebral oxygenation [162]. 13. Follow-Up of Survivors of GM-IVH 12.10. Ethamsylate. Ethamsylate is thought to promote platelet adhesion and increase capillary basement membrane sta- Outpatient follow-up should be done to identify morbidities bility through hyaluronic acid polymerization [163]. A and provide appropriate guidance and treatment through Cochrane Database Systematic Review [164] of 1410 preterm comprehensive neurorehabilitation programs [102]. Given infants from seven trials showed that infants < 35 weeks of the increased risk of PHH, head circumference should be gestation with ethamsylate are significantly less likely to continually monitored [64, 72]. Children with neuropsycho- develop GM-IVH compared to controls. While a significant logical deficits require special support while in school [73] reduction in severe GM-IVH was observed (RR 0.67, 95% with regard to writing, reading, and mathematics. CI 0.49 to 0.94), the review did not show a significant difference in neonatal mortality or neurodevelopmental outcome 14. Conclusion at two years between infants treated with ethamsylate and controls. Thus, routine use of ethamsylate for prevention of In recent years, considerable advances in perinatal-neonatal GM-IVH in preterm infants is not recommended. care have resulted in improved survival outcomes of babies born at the threshold of viability. This has been paralleled 12.11. Phenobarbitone. Earlier observations showed that phe- by a rising number of infants who develop complications nobarbitone may dampen fluctuations in systemic blood such as GM-IVH, a multifactorial neuropathology that exclu- pressure [165] and also protect the brain after hypoxia- sively affects infants of ≤32 weeks’ gestation or those who ischemia. A 2013 Cochrane review conducted by Smit et al. weigh <1500 g at birth. The GM is highly susceptible to hem- [166] involved 12 controlled trials with a sample size of 982 orrhage due to the fragile capillary vasculature coupled with preterm infants. In this study, the effect of phenobarbitone sudden fluctuations in CBF as a result of low mean arterial on the incidence of GM-IVH was controversial, with three pressure and impaired cerebral autoregulatory mechanisms. trials reporting a significant decrease and one trial reporting In light of the high incidence and devastating long-term neu- an increase. Meta-analysis showed that phenobarbitone does rodevelopmental impairment associated with GM-IVH, not reduce the risk of all IVH, severe IVH, PHVD, severe perinatal-neonatal practitioners should optimally utilize the neurodevelopmental impairment, or in-hospital death. Sec- available evidence-based neuroprotective approaches to pre- ondly, there was an increased use of mechanical ventilation vent the occurrence and extension of hemorrhage. More in the phenobarbitone-treated group [166]. Based on this importantly, hospitals should adopt a protocolised schedule strong evidence, postnatal phenobarbitone cannot be recom- using serial real-time CUS to facilitate timely diagnosis of mended for prevention of GM-IVH. GM-IVH. Clinicians should be aware that temporary ventricular decompression can be achieved by VR and VSGS, although 12.12. Recombinant Human Erythropoietin. Early intrave- each has its advantages and disadvantages. There is no evi- nous administration of high-dose recombinant human eryth- dence to support the preference of one intervention technique ropoietin (rhEpo) to very preterm infants (<32 weeks) is safe over another for the temporary management of PHH, which and results in a significantly higher hematocrit, reticulocyte, highlights the need for high-quality collaborative research. and white blood cell counts and a lower platelet count within 7-10 days [167]. Preliminary studies by Fauchere et al. [167, Abbreviations 168] observed no differences between the rhEpo and placebo group with regard to the development of retinopathy of pre- CBF: Cerebral blood flow maturity, IVH, sepsis, NEC, bronchopulmonary dysplasia, CSF: Cerebrospinal fluid and mortality. On the other hand, studies suggest that rhEpo CUS: Cranial ultrasound scan provides neuroprotection to ELBW and very preterm infants DRIFT: Drainage, irrigation, and fibrinolytic therapy with IVH [169, 170]. ELBW: Extremely low birth weight GM: Germinal matrix 12.13. Vitamin E. Vitamin E (tocopherol) is an oxidant that GM-IVH: Germinal matrix-intraventricular hemorrhage scavenges free radicals [163]. In 2003, Brion and colleagues HIV: Human immunodeficiency virus [171] conducted a pooled analysis of twenty-six RCTs to ICP: Intracranial pressure evaluate the effect of Vitamin E supplementation on morbid- LBW: Low birth weight ity and mortality of preterm and LBW infants. Although vita- MRI: Magnetic resonance imaging min E was found to reduce the risk of GM-IVH, it MSC: Mesenchymal stem cells significantly increased the risk of sepsis in preterm infants. NEC: Necrotizing enterocolitis Among VLBW infants, the risk of severe retinopathy was NICU: Neonatal intensive care unit reduced, whereas that of sepsis was increased, respectively. NIRS: Near-infrared spectroscopy However, authors advised caution while interpreting the PHH: Posthemorrhagic hydrocephalus results, as data were heterogeneous and most included stud- PHVD: Posthemorrhagic ventricular dilatation ies were conducted in the 1970s and 1980s, a time during VLBW: Very low birth weight. International Journal of Pediatrics 9

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